Aldose reductase
Encyclopedia
Aldose reductase is an NADPH-dependent oxidoreductase
that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose
to sorbitol
, the first step in polyol pathway
of glucose metabolism.
to sorbitol
, the first step in polyol pathway
of glucose metabolism. The second and last step in the pathway is catalyzed by sorbitol dehydrogenase
, which catalyzes the NAD-linked oxidation of sorbitol to fructose. Thus, the polyol pathway results in conversion of glucose to fructose with stoichiometric utilization of NADPH and production of NADH.
Galactose is also a substrate for the polyol pathway, but the corresponding keto sugar is not produced because sorbitol dehydrogenase is incapable of oxidizing galactitol. Nevertheless, aldose reductase can catalyze the reduction of galactose to galactitol
from glucose; the second step is the oxidation of sorbitol to fructose catalyzed by sorbitol dehydrogenase
. The main pathway from glucose to fructose (glycolysis
) involves phosphorylation
of glucose by hexokinase
to form glucose 6-phosphate, followed by isomerization to fructose 6-phosphate
and hydrolysis
of the phosphate, but the sorbitol pathway is useful because it does not require the input of energy
in the form of ATP
:
Aldose reductase is also present in the lens
, retina
, Schwann cells of peripheral nerves, placenta
and red blood cells.
of aldose reductase in the direction of aldehyde reduction follows a sequential ordered path where NADPH binds, followed by the substrate. Binding of NADPH induces a conformational change (Enzyme•NADPH –> Enzyme*•NADPH) that involves hinge-like movement of a surface loop (residues 213-217) so as to cover a portion of the NADPH in a manner similar to that of a safety belt. The alcohol product is formed via a transfer of the pro-R hydride of NADPH to the re face of the substrate's carbonyl carbon. Following release of the alcohol product, another conformational change occurs (E*•NADP+ –> E•NADP+) in order to release NADP+. Kinetic studies have shown that reorientation of this loop to permit release of NADP+ appears to represent the rate-limiting step in the direction of aldehyde reduction. As the rate of coenzyme release limits the catalytic rate, it can be seen that perturbation of interactions that stabilize coenzyme binding can have dramatic effects on the maximum velocity (Vmax).
The hydride that is transferred from NADP+ to glucose comes from C-4 of the nicotinamide
ring at the base of the hydrophobic cavity. Thus, the position of this carbon defines the enzyme's active site. There exist three residues in the enzyme within a suitable distance of the C-4 that could be potential proton donors: Tyr-48, His-110 and Cys-298. Evolutionary, thermodynamic and molecular modeling evidence predicted Tyr-48 as the proton donor. This prediction was confirmed the results of mutagenesis studies. Thus, a [hydrogen-bonding] interaction between the phenolic hydroxyl group of Tyr-48 and the ammonium side chain of Lys-77 is thought to help to facilitate hydride transfer.
is recognized as a leading cause of new cases of blindness, and is associated with increased risk for painful neuropathy, heart disease and kidney failure. Many theories have been advanced to explain mechanisms leading to diabetic complications, including stimulation of glucose metabolism by the polyol pathway. Additionally, the enzyme is located in the eye (cornea
, retina
, lens
), kidney
, and the myelin sheath–tissues that are often involved in diabetic complications. Under normal glycemic conditions, only a small fraction of glucose is metabolized through the polyol pathway, as the majority is phosphorylated by hexokinase, and the resulting product, glucose-6-phosphate, is utilized as a substrate for glycolysis or pentose phosphate metabolism. However, in response to the chronic hyperglycemia
found in diabetics, glucose flux through the polyol pathway is significantly increased. Up to 33 % of total glucose utilization in some tissues can be through the pymol pathway.
Glucose concentrations are often elevated in diabetics and aldose reductase has long been believed to be responsible for diabetic complications involving a number of organs. Many aldose reductase inhibitor
s have been developed as drug candidates but virtually all have failed although some such as epalrestat
are commercially available in several countries. Additional reductase inhibitors such as ranirestat
, ponalrestat, rinalrestat, risarestat, sorbinil
, and berberine
are currently in clinical trials.
Oxidoreductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule to another...
that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
to sorbitol
Sorbitol
Sorbitol, also known as glucitol, Sorbogem® and Sorbo®, is a sugar alcohol that the human body metabolizes slowly. It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group. Sorbitol is found in apples, pears, peaches, and prunes...
, the first step in polyol pathway
Polyol pathway
Also called the sorbitol-aldose reductase pathway, the polyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina, kidney, and nerves....
of glucose metabolism.
Reactions
Aldose reductase catalyzes the NADPH-dependent conversion of glucoseGlucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
to sorbitol
Sorbitol
Sorbitol, also known as glucitol, Sorbogem® and Sorbo®, is a sugar alcohol that the human body metabolizes slowly. It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group. Sorbitol is found in apples, pears, peaches, and prunes...
, the first step in polyol pathway
Polyol pathway
Also called the sorbitol-aldose reductase pathway, the polyol pathway appears to be implicated in diabetic complications, especially in microvascular damage to the retina, kidney, and nerves....
of glucose metabolism. The second and last step in the pathway is catalyzed by sorbitol dehydrogenase
Sorbitol dehydrogenase
Sorbitol dehydrogenase is a protein. In humans this protein is encoded by the SORD gene.Sorbitol dehydrogenase is an enzyme in carbohydrate metabolism converting sorbitol, the sugar alcohol form of glucose, into fructose. Together with aldose reductase, it provides a way for the body to produce...
, which catalyzes the NAD-linked oxidation of sorbitol to fructose. Thus, the polyol pathway results in conversion of glucose to fructose with stoichiometric utilization of NADPH and production of NADH.
- glucoseGlucoseGlucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
+ NADPH + H+ → sorbitolSorbitolSorbitol, also known as glucitol, Sorbogem® and Sorbo®, is a sugar alcohol that the human body metabolizes slowly. It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group. Sorbitol is found in apples, pears, peaches, and prunes...
+ NADP+
Galactose is also a substrate for the polyol pathway, but the corresponding keto sugar is not produced because sorbitol dehydrogenase is incapable of oxidizing galactitol. Nevertheless, aldose reductase can catalyze the reduction of galactose to galactitol
- galactoseGalactoseGalactose , sometimes abbreviated Gal, is a type of sugar that is less sweet than glucose. It is a C-4 epimer of glucose....
+ NADPH + H+ → galactitol + NADP+
Function
The aldose reductase reaction, in particular the sorbitol produced, is important for the function of various organs in the body. For example, it is generally used as the first step in a synthesis of fructoseFructose
Fructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
from glucose; the second step is the oxidation of sorbitol to fructose catalyzed by sorbitol dehydrogenase
Sorbitol dehydrogenase
Sorbitol dehydrogenase is a protein. In humans this protein is encoded by the SORD gene.Sorbitol dehydrogenase is an enzyme in carbohydrate metabolism converting sorbitol, the sugar alcohol form of glucose, into fructose. Together with aldose reductase, it provides a way for the body to produce...
. The main pathway from glucose to fructose (glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
) involves phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of glucose by hexokinase
Hexokinase
A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate the most important product....
to form glucose 6-phosphate, followed by isomerization to fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
and hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of the phosphate, but the sorbitol pathway is useful because it does not require the input of energy
Energy
In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...
in the form of ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
:
- Seminal vesicleSeminal vesicleThe seminal vesicles or vesicular glands are a pair of simple tubular glands posteroinferior to the urinary bladder of male mammals...
s: Fructose produced from sorbitol is used by the sperm cellsSpermatozoonA spermatozoon is a motile sperm cell, or moving form of the haploid cell that is the male gamete. A spermatozoon joins an ovum to form a zygote...
. - LiverLiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
: Fructose produced from sorbitol can be used as an energy source for glycolysis and glyconeogenesis.
Aldose reductase is also present in the lens
Lens (anatomy)
The crystalline lens is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. The lens, by changing shape, functions to change the focal distance of the eye so that it can focus on objects at various distances, thus allowing a...
, retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, Schwann cells of peripheral nerves, placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
and red blood cells.
Enzyme Structure
Aldose reductase may be considered a prototypical enzyme of the aldo-keto reductase enzyme superfamily. The enzyme comprises 315 amino acid residues and folds into a β/α-barrel structural motif composed of eight parallel β strands. Adjacent strands are connected by eight peripheral α-helical segments running anti-parallel to the β sheet. The catalytic active site situated in the barrel core. The NADPH cofactor is situated at the top of the β/α barrel, with the nicotinamide ring projects down in the center of the barrel and pyrophosphate straddling the barrel lip.Enzyme Mechanism
The reaction mechanismReaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
of aldose reductase in the direction of aldehyde reduction follows a sequential ordered path where NADPH binds, followed by the substrate. Binding of NADPH induces a conformational change (Enzyme•NADPH –> Enzyme*•NADPH) that involves hinge-like movement of a surface loop (residues 213-217) so as to cover a portion of the NADPH in a manner similar to that of a safety belt. The alcohol product is formed via a transfer of the pro-R hydride of NADPH to the re face of the substrate's carbonyl carbon. Following release of the alcohol product, another conformational change occurs (E*•NADP+ –> E•NADP+) in order to release NADP+. Kinetic studies have shown that reorientation of this loop to permit release of NADP+ appears to represent the rate-limiting step in the direction of aldehyde reduction. As the rate of coenzyme release limits the catalytic rate, it can be seen that perturbation of interactions that stabilize coenzyme binding can have dramatic effects on the maximum velocity (Vmax).
The hydride that is transferred from NADP+ to glucose comes from C-4 of the nicotinamide
Nicotinamide
Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...
ring at the base of the hydrophobic cavity. Thus, the position of this carbon defines the enzyme's active site. There exist three residues in the enzyme within a suitable distance of the C-4 that could be potential proton donors: Tyr-48, His-110 and Cys-298. Evolutionary, thermodynamic and molecular modeling evidence predicted Tyr-48 as the proton donor. This prediction was confirmed the results of mutagenesis studies. Thus, a [hydrogen-bonding] interaction between the phenolic hydroxyl group of Tyr-48 and the ammonium side chain of Lys-77 is thought to help to facilitate hydride transfer.
Role in diabetes
Diabetes mellitusDiabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
is recognized as a leading cause of new cases of blindness, and is associated with increased risk for painful neuropathy, heart disease and kidney failure. Many theories have been advanced to explain mechanisms leading to diabetic complications, including stimulation of glucose metabolism by the polyol pathway. Additionally, the enzyme is located in the eye (cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
, retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
, lens
Lens (anatomy)
The crystalline lens is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. The lens, by changing shape, functions to change the focal distance of the eye so that it can focus on objects at various distances, thus allowing a...
), kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, and the myelin sheath–tissues that are often involved in diabetic complications. Under normal glycemic conditions, only a small fraction of glucose is metabolized through the polyol pathway, as the majority is phosphorylated by hexokinase, and the resulting product, glucose-6-phosphate, is utilized as a substrate for glycolysis or pentose phosphate metabolism. However, in response to the chronic hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
found in diabetics, glucose flux through the polyol pathway is significantly increased. Up to 33 % of total glucose utilization in some tissues can be through the pymol pathway.
Glucose concentrations are often elevated in diabetics and aldose reductase has long been believed to be responsible for diabetic complications involving a number of organs. Many aldose reductase inhibitor
Aldose reductase inhibitor
Aldose reductase inhibitors are a class of drugs being studied as a way to prevent eye and nerve damage in people with diabetes.-Mechanism:Their target, aldose reductase, is an enzyme that is normally present in many other parts of the body, and catalyzes one of the steps in the sorbitol pathway...
s have been developed as drug candidates but virtually all have failed although some such as epalrestat
Epalrestat
Epalrestat is an aldose reductase inhibitor."Long-term treatment with epalrestat is well tolerated and can effectively delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease, particularly in subjects with good glycemic control and limited...
are commercially available in several countries. Additional reductase inhibitors such as ranirestat
Ranirestat
Ranirestat is an aldose reductase inhibitor being developed for the treatment of diabetic neuropathy by Dainippon Sumitomo Pharma and PharmaKyorin. It has been granted orphan drug status. The drug is to be used orally.-Trials:...
, ponalrestat, rinalrestat, risarestat, sorbinil
Sorbinil
Sorbinil is an aldose reductase inhibitor being investigated for treatment of diabetic complications including neuropathy and retinopathy....
, and berberine
Berberine
Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary ammonium salt from the protoberberine group of isoquinoline alkaloids. It is found in such plants as Berberis Berberine is a quaternary...
are currently in clinical trials.